Methods for treatment of pelvic pain and/or comorbid conditions

ABSTRACT

Methods, systems, devices, and medicaments are provided for locally administering to a pelvic-area organ or tissue structure in a patient at least one drug continuously or continually over a treatment period of 24 hours or more in an amount effective to achieve a therapeutic effect in another organ or tissue structure by means of shared or convergent pelvic afferent pathways. The methods systems, devices, and medicaments can be used in the treatment of IC/BPS, chronic pelvic pain, vulvodynia, orchialgia, urethral syndrome, dysparenia, chronic prostatitis, chronic pelvic pain, levator ani syndrome, irritative bowel syndrome, or a combination thereof. The drug may include anesthetic agents, analgesic agents, antispasmodic agents, antimuscarinic agents, and combinations thereof. The drug may be released from a drug delivery device or a sustained release composition deployed inside the bladder.

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority benefit is claimed to U.S. provisional patent application No.61/640,368, filed Apr. 30, 2012. The application is incorporated hereinby reference.

FIELD OF THE INVENTION

This disclosure is generally in the field of methods and systems fortreating chronic pelvic pain, and more particularly to methods andsystems for a sustained treatment effect.

BACKGROUND

Studies have shown that proper pelvic physiologic function requires thecoordination of complex integrative sensory pathways. These pathways mayconverge peripherally, centrally, or both (see Ustinova, E., et al.NEUROUROLOGY AND URODYNAMICS 29, 2010, 77-81). Sensitized convergentpelvic afferent pathways have been demonstrated in animal models ofcolitis and cystitis where inducing an inflammatory disease state in oneorgan produced lower sensory thresholds in the other. For example, theelimination of pain in one organ, such as the bladder, may reduce thepain in another organ.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a urologicalcondition characterized by pain, increased urinary frequency, andurgency. This condition may also involve varying degrees of urinaryincontinence and sexual dysfunction. IC/BPS include patients withurinary pain not attributable to other causes, such as infection orurinary stones, and are estimated to affect approximately 3 to 8 millionpeople in the U.S. alone, the majority of whom are women (Berry 2009).IC/BPS is a serious condition with unmet medical needs.

There is also a need to treat pelvic pain, including bladder pain,levator ani syndrome, and irritative voiding symptoms in non-IC/BPSpatients. Non-limiting examples of such non-IC/BPS patients includepatients with ureteral stents or neurogenic conditions.

In addition, there is a need to treat chronic pelvic pain, vulvodynia,irritable bowel syndrome, and dyspareunia, among other pelvic paindisorders. High rates of comorbidities are found in IC/BPS patients.

Current treatments for pelvic pain, including bladder pain, include butare not limited to oral medications, such as antimuscarinics, alphablockers, tricyclics antidepressents, antispasmodics, SSRIs, pentosanpolysulfate sodium, and gabapentin. These drugs may not be effective forsome patients. In addition, these oral drugs are delivered systemically,which may cause unwanted side effects and may not achievetherapeutically effective levels in the bladder when at acceptableplasma levels.

Another current treatment includes instillation of a drug (e.g.,lidocaine, other “caine” anesthetic agents) solution directly into thebladder. Other instillations, such as dimethyl sulfoxide (DMSO),antimuscarinics, heparin, are also known. Another available procedure ishydrodistention. Botox injection or instillation is also available. Noneof these treatments have been shown to be widely effective or to providea sustained therapeutic benefit.

A number of studies of instillation procedures with lidocaine have beenperformed in recent years. Nickel et al., BJU International, 103:910-918(2008) discloses a study in which patients with IC/PBS were studied in arandomized, placebo controlled, double blind fashion, evaluating theeffect of 5 daily instillations of an alkalinized solution of lidocaine(200 mg) on efficacy measures of bladder pain and irritative voidingsymptoms on Day 8 (three days after completion of treatment) and Day 15(ten days after completion of treatment.) One efficacy measure thatshowed improvement at Day 8 (the Interstitial Cystitis Symptom Index orICSI) did not show sustained improvement at Day 15. Other efficacymeasures (bladder pain, urgency, voiding frequency) never showedimprovement following treatment when measured either at Day 8 and Day 15(bladder pain) or only at Day 15 (urgency, voiding frequency). Oneefficacy measure called the Interstitial Cystitis Problem Index (ICPI)showed improvement both at Day 8 and Day 15, but the effect at Day 15had diminished somewhat. These findings suggest that instillations oflidocaine into the bladder, even when administered on an aggressiveschedule of daily instillation, were not able to show a sustainedtreatment effect out to 10 days following treatment.

Parsons, Urology 65(1):45-48 (2005) discloses a study in which patientswith IC were treated with instillations of alkalinized lidocaine andheparin into the bladder as a single one hour treatment, then followedfor 48 hours to assess duration of effect. The paper describes that 94%of patients had relief at 20 minutes following instillation, 50% at 4hours and 3 of 28 patients (FIG. 1) or ˜10% at 48 hours, suggesting awaning of effect over time. Additionally, a set of patients who receivedthree instillations a week for two weeks were assessed at 48 hoursfollowing last treatment for durability of effect; 80% reported reliefof symptoms; no further follow-up is provided. These findings suggestthat the durability of treatment effect for a single lidocaineinstillation is approximately 10% at 48 hours.

Henry, et al., J Urology 165:1900-03 (2001) discloses a study in whichlidocaine instillations were used in both healthy volunteers (forpharmacokinetic purposes) and IC patients. Pain assessments following asingle lidocaine instillation showed duration of effect to beapproximately 24 hours: the mean pain score prior to treatment was 6.0Immediately following treatment this decreased to 1.8. The next day,mean pain had increased up to 3.7. This was again reduced to 1.2 with asecond instillation. These results support those seen in the Parsons andNickel publications, suggesting that the duration of treatment effectwith intravesical solutions of lidocaine are 24 to 48 hours.

It would be desirable to provide improved methods for treating patientssuffering from IC/BPS, chronic pelvic pain, vulvodynia, irritable bowelsyndrome, levator ani syndrome, dyspareunia, or combinations of theseconditions. It would also be desirable to treat other types of pelvicpain. It would be desirable to provide a sustained treatment effect forseveral days or weeks or more beyond the active treatment period andbeyond the local treatment site. It would also be desirable to reducethe number of invasive procedures, such as instillation procedures,needed to achieve a sustained treatment effect, in particular whilereducing the side effects associated with systemic administration ofdrugs that are potentially effective in treating one or more of theforegoing pelvic disorders.

SUMMARY

Method of treating a patient are provided that include locallyadministering to a pelvic-area organ or tissue structure in the patientat least one drug continuously or continually over a treatment period of24 hours or more in an amount effective to achieve a therapeutic effectin another organ or tissue structure by means of shared or convergentpelvic afferent pathways. The pelvic-area organ or tissue structure maycomprise the bladder. The drug may comprise an anesthetic agent, ananalgesic agent, an antispasmodic agent, an antimuscarinic agent, or acombination thereof. In one embodiment, the drug is released from a drugdelivery device or a sustained release composition deployed inside thepatient's bladder. The method may be used to treat a patient diagnosedto have one or more of the following: IC/BPS, chronic pelvic pain,vulvodynia, orchialgia, endometriosis, urethral syndrome, dysparenia,chronic prostatitis, chronic pelvic pain, levator ani syndrome,irritative bowel syndrome, or a combination thereof.

In embodiments, the therapeutic effect comprises favorably affectingsensory nerve ganglia resulting in reduced pain, improvement of one ormore symptoms, or both. The sensory nerve ganglia, in some embodiments,may be associated with sites that are not directly contacted by thedrug. For instance, by delivering a lidocaine or other drug to thebladder continuously or continually for an extended period, diseases orconditions in tissues distant from the bladder may be ameliorated orcured by means of shared or convergent pelvic afferent pathways.

In some embodiments, the continuous treatment, such as over multipledays, is effective to provide an extended benefit beyond the end oftreatment. For example, locally administering lidocaine or anotheranesthetic or analgesic agent locally to a pelvic area organ or tissuestructure in the patient in an amount effective to achieve a measurableplasma concentration of the drug in the patient continuously over atreatment period of at least 24 hours may achieve a reduction of bladderpain and irritative voiding symptoms that is sustained well beyond theend of the active treatment period.

In another embodiment, the therapeutic effect comprises local healing ofulcerative lesions—for example, in the bladder—to reduce pain or improveone or more symptoms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of an embodiment of a drug delivery device.

FIG. 2 is a plan view of the drug delivery device shown in FIG. 1,illustrating the drug delivery device inside a deployment instrument.

FIG. 3 is a cross-sectional view of the drug delivery device shown inFIG. 1, taken along line 3-3 in FIG. 1.

FIG. 4 is an illustration showing the size of an embodiment of a drugdelivery device in comparison to an approximation of the bladder trigoneregion.

FIG. 5 illustrates examples of shapes for a retention frame of a drugdelivery device.

FIG. 6 illustrates examples of configurations for drug delivery deviceshaving at least one drug delivery portion and a retention frame portion.

FIG. 7 illustrates a method of implanting a drug delivery device.

FIG. 8 is a sagittal view of a male patient, illustrating a drugdelivery device exiting a deployment instrument into a bladder of thepatient.

FIG. 9 is a detailed cross-sectional plan view of an embodiment of adrug delivery device.

FIG. 10 is a detailed cross-sectional plan view of another embodiment ofa drug delivery device.

FIGS. 11-14 are graphs showing various baseline improvement scoresachieved with an embodiment of a drug delivery device.

FIGS. 15-19 are graphs showing various index scores achieved with anembodiment of a drug delivery device.

FIG. 20 is a graph showing cumulative release of lidocaine over atreatment period, according to one embodiment.

FIG. 21 is a graph showing lidocaine release rate according to oneembodiment.

FIG. 22 is a graph showing cumulative release of lidocaine over atreatment period, according to one embodiment.

FIG. 23 is a graph showing lidocaine release according to oneembodiment.

DETAILED DESCRIPTION

It has been discovered that a sustained treatment effect on pelvic paincan be achieved by providing to a pelvic-area organ or tissue structure,such as a the bladder or other lumenal structure, continuous treatmentwith an anesthetic agent, an analgesic agent, an antispasmodic agent, anantimuscarinic agent, or a combination thereof over a period of 24 hoursor more. In one embodiment, the drug comprises lidocaine or othercocaine analogue or another anesthetic agent. Essentially any means oflocally delivering the drug into the pelvic-area tissue site can be usedso long as provides a therapeutically effective amount of the drug tothe tissue site continuously over the treatment period of 24 hours ormore. The continuous treatment, e.g., with lidocaine or anotheranesthetic agent or analgesic, over multiple days is effective toprovide the patient with pain relief during the treatment period, butalso surprisingly provides an extended benefit well beyond the end oftreatment.

As used herein, the term “continuous” or “continuously” in reference tothe act of administering to the patient therapeutically effectiveamounts of the drug for treatment means includes constant or continualrelease or intermittent release so long as a non-zero plasma level ofthe lidocaine or other anesthetic agent is maintained over the treatmentperiod, e.g., at least 24 hours. As used herein, the phrases “non-zeroplasma level” and “measurable plasma concentration” refer to the lowlimit of detection using the bioanalytical HPLC method as known in theart.

In an alternative embodiment, the drug may be released intermittently(for example every 8 hours) but continually during a treatment period of24 hours or more, wherein there may be subperiods in which plasmaconcentration levels of the drug briefly fall to undetectable levels.While this is not considered continuous administration of the drug, itmay be therapeutically effective with the combined releases beingcontinual over the treatment period and measurable plasma concentrationsof the drug being maintained over more than 50%, preferably more than80%, more preferably more than 90%, of the treatment period.

As used herein, the phrases “amount effective to achieve a therapeuticeffect which is sustained beyond the end of the treatment period”,“sustained treatment effect”, or “sustained therapeutic effect” refer toand include at least a 20% improvement or baseline reduction in at leastone of the following 7 or more days after the treatment period ends:baseline pain, baseline bladder urgency, or increases in the number ofpatients scoring their symptoms as “moderately improved” or “markedlyimproved” in a Global Response Assessment (GRA) test. The GRA test andpain test may be directed to any pain in the pelvic area, includingbladder pain or other pains, including those caused by the co-morbidconditions described herein.

In certain embodiments, at least a 35% reduction of baseline pain 7 ormore days after the treatment period ends may be achieved. In oneembodiment, at least a 40% reduction of baseline pain 7 or more daysafter the treatment period ends may be achieved. In another embodiment,at least a 45% reduction of baseline pain 7 or more days after thetreatment period ends may be achieved. In a further embodiment, at leasta 50% reduction of baseline pain 7 or more days after the treatmentperiod ends may be achieved. In the embodiments of this paragraph, themeasured reductions refer to results from to an open label trial orstudy.

In certain embodiments, at least a 45% reduction of baseline bladderurgency 7 or more days after the treatment period ends may be achieved.In one embodiment, at least a 50% reduction of baseline bladder urgency7 or more days after the treatment period ends may be achieved. Inanother embodiment, at least a 55% reduction of baseline bladder urgency7 or more days after the treatment period ends may be achieved. In afurther embodiment, at least a 60% reduction of baseline bladder urgency7 or more days after the treatment period ends may be achieved. In theembodiments of this paragraph, the measured reductions refer to resultsfrom to an open label trial or study.

As used herein, the term “pelvic-area organ or tissue structure”includes the bladder and other lumenal tissues, including those in thegenitourinary and lower gastrointestinal sites, particularly thosepelvic organs and structures that communicate through nerve connectionsor reflexes either directly or via convergent pathways (e.g., pathwaysthat meet in controlled areas such as the lumbosacral or lower spinalcord).

In one embodiment, the lidocaine or other anesthetic agent isadministered to a pelvic-area organ or tissue structure, such as alumen, that is associated with an organ that is diseased or otherwisecauses one or more of the patient's symptoms. In another embodiment, thelidocaine or other anesthetic agent is administered to a pelvic-areaorgan or tissue structure, such as a lumen, that is not associated withan organ that is diseased or otherwise causing the patient's symptoms.

In some embodiments, the drug provides a therapeutic effect in thepelvic-area organ or tissue structure in which the drug is administered.In other embodiments, the drug provides a therapeutic effect in thepelvic-area organ or tissue structure in which the drug is administered,and in at least one other organ or region of the pelvic area. In furtherembodiments, the drug does not provide a therapeutic effect in thepelvic-area organ or tissue structure in which drug is administered, butdoes provide a therapeutic effect in at least one other organ or regionof the pelvic area. In one embodiment, a therapeutic effect is providedby pelvic afferent neuronal crosstalk, cross-sensitization, or both, inat least one other organ or region of the pelvic area in which thelidocaine or other anesthetic agent is not administered. In oneembodiment, diffusion of the drug out of the pelvic-area organ or tissuestructure into which they are disposed provides a therapeutic effect forthe at least one other organ or region of the pelvic area in which thelidocaine or other anesthetic agent is not administered.

As used herein, the terms “pelvic afferent neuronal crosstalk” and“cross-sensitization” refer to phenomena that cause a particulartreatment to impact diseases or symptoms outside the zone of treatment.Due to these phenomena, treatment of one disease or symptom in one organor region of the pelvic-area may cure or improve another disease orsymptom in an untreated second organ or region of the pelvic area. Inone embodiment, favorably affecting sensory nerve ganglia in one organor region achieves similar results in another organ or region. Forexample, treatment of one co-morbid disease in the pelvic area may cureor lessen the symptoms associated with another co-morbid disease.Examples of co-morbid diseases that originate or cause symptoms in thepelvic area include IC/BPS, irritable bowel syndrome (IBS), vulvodynia,orchialgia, levator ani syndrome, urethral syndrome, and chronicprostatitis.

In one embodiment, the continuous treatment may be provided by deployinga drug delivery device into the bladder or other pelvic-area organ ortissue structure of the patient that can release lidocaine into thebladder or other pelvic-area organ or tissue structure continuously overa period greater than one day, for example from 2 to 28 days, from 3 to21 days, or from 10 to 14 days. In one embodiment, the method includesreleasing a mean average of from about 10 mg to about 26 mg lidocaine(FBE) per day (e.g., about 11 mg, about 12 mg per day) over a 14-daytreatment period.

In one particular variation of this embodiment, the cumulative amount oflidocaine (FBE) released continuously over a 14-day period isapproximately 130 mg. In one embodiment, the rate of lidocaine (FBE)released into the bladder from the device over this period is from 15 mgto 30 mg day per day over the first 1 to 4 days and then tapering off,for example at a rate of from 15 mg to 3 mg per day over the remainderof the active treatment period. At the end of the treatment period, thedevice can be retrieved from the bladder.

In one embodiment where lidocaine is administered, the measurable plasmaconcentration of lidocaine does not exceed 65 ng/ml at a time of peaklidocaine exposure in the bladder, for example with the 650 mg lidocainedevice described in Example 2 below. With smaller payload devices orsystems releasing lidocaine at a lower rate, the measurable plasmaconcentration of lidocaine at a time of peak lidocaine exposure may beeven lower, for example not exceeding 50 ng/ml, 40 ng/ml, 25 ng/ml, or15 ng/ml. In other cases, the measurable plasma concentration oflidocaine may exceed 65 ng/ml at a time of peak lidocaine exposure.

In another embodiment, the continuous treatment may be include pumping alidocaine solution into the pelvic-area organ or tissue structurethrough a urethral or suprapubic catheter in a continuous or pulsatilemanner over the treatment period. It is noted that a single instillation(bolus) of lidocaine per day would not be expected to provide continuoustreatment over a 24-hour period, as the patient would be likely tourinate away any unabsorbed lidocaine before the end of the period. Instill another embodiment, a coating substance may be locally applied tothe pelvic-area lumen wall, wherein the coating substance includeslidocaine and one or more excipient materials that promote adherence ofthe coating substance to the wall of the pelvic-area organ or tissuestructure and provides continuous controlled release of the lidocaineover the treatment period.

In some embodiments, the coating substance is a mucoadhesiveformulation. Examples of mucoadhesive formulations include, but are notlimited to, gels, ointments, creams, films, emulsion gels, tablets,polymers, or a combination thereof. Mucoadhesive formulation polymersmay include hydrogels or hydrophilic polymers, polycarbophil (i.e.Carbopols, etc.), chitosan, polyvinylpyrrolidone (PVP), lectin,polyethyleneglycolated polymers, celluloses, or a combination thereof.Suitable celluloses include methyl cellulose (MC), carboxymethylcellulose (CMC), hydroxypropyl cellulose (HPC), or combinations thereof.

In some embodiments, the coating substance is or can include apermeation enhancer. Non-limiting examples of permeation enhancersinclude dimethyl sulfoxide (DMSO), sodium carboxymethyl cellulose(NaCMC), lipids, surfactants, or combinations thereof.

In other embodiments, the method may include releasing or pumping agreater or lesser cumulative amount of lidocaine over the treatmentperiod.

It is also envisioned that a topical sustained release system, such as atransdermal patch, may be used to continuously deliver the lidocaine orother anesthetic agent regionally or systemically to a patient in needof treatment for 24 hours or more to achieve a sustained treatmenteffect.

The devices and methods disclosed herein build upon those described inU.S. application Ser. No. 12/825,215, filed Jun. 28, 2010 (TB 101); U.S.Pat. No. 8,343,516, issued Jan. 1, 2013 (TB 102); and U.S. applicationSer. No. 12/851,494, filed Aug. 5, 2010 (TB 108), which are incorporatedherein by reference.

The term “patient” refers to humans, whether male or female, adult orchild. The methods and devices also may be used with other mammals, suchas in veterinary or livestock applications.

The Implantable Drug Delivery Device

An embodiment of a drug delivery device 100 is illustrated in FIG. 1.The device 100 includes a drug reservoir portion 102 and a retentionframe portion 104. In FIG. 1, the device 100 is shown in a relativelyexpanded shape suited for retention in the body, and in FIG. 2 thedevice 100 is shown in a relatively lower-profile shape for deploymentthrough the channel 200 of a deployment instrument, such as a cystoscopeor other catheter. Following deployment into the body of a patient, thedevice 100 may assume the relatively expanded shape to retain the drugdelivery device in the pelvic area organ or tissue structure, such asthe bladder or other lumen.

For the purposes of this disclosure, terms such as “relatively expandedshape”, “relatively higher-profile shape”, or “retention shape”generally denote any shape suited for retaining the device in theintended implantation location, including but not limited to the pretzelshape shown in FIG. 1 that is suited for retaining the device in thebladder or may be modified for another pelvic-area lumen. Similarly,terms such as “relatively lower-profile shape” or “deployment shape”generally denote any shape suited for deploying the drug delivery deviceinto the body, including the linear or elongated shape shown in FIG. 2that is suited for deploying the device through the working channel ofcatheter, cystoscope, or other deployment instrument positioned in alumen of the body, such as the urethra. The drug delivery device maynaturally assume the relatively expanded shape and may be deformed,either manually or with the aid of an external apparatus, into therelatively lower-profile shape for insertion into the body. Oncedeployed the device may spontaneously or naturally return to theinitial, relatively expanded shape for retention in the body.

In the illustrated embodiment, the drug reservoir and retention frameportions 102, 104 of the drug delivery device 100 are longitudinallyaligned and are coupled to each other along their length, although otherconfigurations are possible. For example, the drug reservoir portion 102may be attached to the retention frame portion 104 at discrete pointsbut otherwise may be separate or spaced apart from the retention frameportion 104.

In particular, the drug delivery device 100 includes an elastic orflexible device body 106 that defines a drug reservoir lumen 108 and aretention frame lumen 110. The drug reservoir lumen 108 is designed tohouse a drug formulation, such as a number of solid drug tablets 112, toform the drug reservoir portion 102. The retention frame lumen 110 isdesigned to house a retention frame 114 to form the retention frameportion 104. The illustrated lumens 108, 110 are discrete from eachother, although other configurations are possible.

As shown in the cross-sectional view of FIG. 3, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The device body 106 maybe formed integrally, such as via molding or extrusion, althoughseparate construction and assembly of the tubes 122, 124 is possible.The wall 124 that defines the retention frame lumen 110 may extend alongthe entire length of the wall 122 that defines the drug reservoir lumen108, so that the retention frame lumen 110 has the same length as thedrug reservoir lumen 108 as shown, although one wall may be shorter thanthe other wall in other embodiments. The two walls 122, 124 are attachedalong the entire length of the device in the illustrated embodiment,although intermittent attachment can be employed.

An aperture 118 may be formed through the wall 124 that defines the drugreservoir lumen 108. The aperture 118 may provide a passageway forreleasing drug from the drug reservoir lumen 108 as further describedbelow. However, the aperture 118 may be omitted in some embodiments.

As shown in FIG. 1, the drug reservoir lumen 108 is loaded with a numberof drug units 112 in a serial arrangement. For example, between about 10and about 100 drug units 112 may be loaded. However, any number of drugunits may be used. The drug reservoir lumen 108 includes an entry 130and an exit 132, which are shown as relatively circular openings atopposite ends of the drug reservoir lumen 108. The entry 130 providesingress for the drug units 112 to be placed into the drug reservoirlumen 108 during device loading and assembly. Once the drug units 112are loaded, end plugs 120 block the entry 130 and exit 132. The endplugs 120 may be cylindrical plugs inserted into the entry 130 and theexit 132, each having a slightly larger outer diameter than an innerdiameter of the drug reservoir lumen 108 so that the plugs substantiallyenclose the entry 130 and exit 132 and are snugly retained in position.The end plugs 120 may be silicone plugs. The end plugs 120 also may beomitted, in which case the entry 130 and exit 132 may be closed with amaterial, such as adhesive, that is placed in the drug reservoir lumen108 in workable form and cures therein. One or both end plugs mayinclude an aperture for release of solubilized drug in vivo.

Once the drug units 112 are loaded, interstices 116 or breaks may beformed between adjacent drug units 112. The interstices or breaks 116may serve as reliefs that accommodate deformation or movement of thedevice 100, while permitting the individual drug units 112 to retaintheir solid form during storage and deployment. Thus, the drug deliverydevice 100 may be relatively flexible or deformable despite being loadedwith a solid drug, as each drug unit 112 may be permitted to move withreference to adjacent drug units 112. Along the length of the devicedrug reservoir lumen 108, the drug units 112 may have the samecomposition or may vary in composition, and in some cases drug units 112of different compositions may be in distinct reservoirs that aresegregated, either axially or radially, along the length of the drugreservoir lumen 108.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire. The elastic wire functions as a spring.The retention frame 110 may be configured to spontaneously return to aretention shape, such as the illustrated “pretzel” shape or anothercoiled shape. In particular, the retention frame 114 may retain thedevice 100 in the body, such as in the bladder. For example, theretention frame 114 may have an elastic limit and modulus that allowsthe device 100 to be introduced into the body in a relativelylower-profile shape, permits the device 100 to return the relativelyexpanded shape once inside the body, and impedes the device fromassuming the relatively lower-profile shape within the body in responseto expected forces, such as the hydrodynamic forces associated withcontraction of the detrusor muscle and urination. Thus, the device 100may be retained in the body once implanted, limiting or preventaccidental expulsion.

The material used to form the device body 106 may be elastic or flexibleto permit moving the device 100 between deployment and retention shapes.When the device is in the retention shape, the retention frame portion104 may tend to lie inside the drug reservoir portion 102 as shown,although the retention frame portion 104 can be positioned inside,outside, above, or below the drug reservoir portion 102 in other cases.The flexible material also allows the device body 106 to flex outward orcircumferentially expand in response to a flow of pressurized gasthrough the drug reservoir lumen 108 during drug loading, as describedbelow. The material used to form the device body 106 also may be waterpermeable or porous so that solubilizing fluid (e.g., water) can enterthe drug reservoir portion 102 to solubilize the drug units 112 once thedevice is implanted. For example, silicone or another biocompatibleelastomeric material may be used.

In one embodiment in which the drug delivery device 100 is designed tobe implanted in the bladder, the drug delivery device 100 is designed tobe inserted into (and optionally retrieved from) the bladder through theurethra. Thus, the device may be sized and shaped to fit through anarrow tubular path of a deployment instrument, such as a catheter orcystoscope.

Typically, a cystoscope for an adult human has an outer diameter ofabout 5 to 7 mm and a working channel having an inner diameter of about2.4 mm to about 2.6 mm. In other embodiments, a cystoscope has a workingchannel with a larger inner diameter, such as an inner diameter of 4 mmor more. Thus, the device may be relatively small in size. For example,when the device is elastically deformed to the relatively lower profileshape, the device for an adult patient may have a total outer diameterthat is about 3.75 mm or less, such as about 2.6 mm or less. Forpediatric patients, the dimensions of the device are anticipated to besmaller. In addition to permitting insertion, the relatively small sizeof the device may also reduce patient discomfort and trauma to thebladder.

The overall configuration of the device preferably is designed to ensurethat the device is tolerable to the patient while it is deployed invivo, as described in U.S. Patent Application Publication No.2011/0152839 A1 to Cima et al., which is incorporated herein byreference. The device geometry may be customized to avoid or minimizedundesirable contact forces and pressures linked to urgency sensation.Within the three-dimensional space occupied by the device in theretention shape, the maximum dimension of the device in any direction isless than 10 cm, the approximate diameter of the bladder when filled. Insome embodiments, the maximum dimension of the device in any directionmay be less than about 9 cm, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particular embodiments, themaximum dimension of the device in any direction is less than about 7cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm orsmaller. In preferred embodiments, the maximum dimension of the devicein any direction is less than about 6 cm or smaller.

More particularly, the three-dimension space occupied by the device isdefined by three perpendicular directions. Along one of these directionsthe device has its maximum dimension, and along the two other directionsthe device may have smaller dimensions. For example, the smallerdimensions in the two other directions may be less than about 4 cm, suchas about 3.5 cm, 3 cm, or less. In a preferred embodiment, the devicehas a dimension in at least one of these directions that is less than 3cm.

The overall shape of the device may enable the device to reorient itselfwithin the bladder to reduce its engagement or contact with the bladderwall. For example, the overall exterior shape of the device may becurved, and all or a majority of the exterior or exposed surfaces of thedevice may be substantially rounded. The device also may besubstantially devoid of sharp edges, and its exterior surfaces may beformed from a material that experiences reduced frictional engagementwith the bladder wall. Such a configuration may enable the device toreposition itself within the empty bladder so that the device applieslower contact pressures to the bladder wall. In other words, the devicemay slip or roll against the bladder wall into a position in which thedevice experiences less compression. In embodiments, the device is notfixed to one location within the bladder, i.e., it may move freelywithin the bladder, which without being bound to any particular theoryis believed at least in part to contribute to the device's quality ofbeing tolerable or even unnoticeable in human bladders.

An example of a device that generally satisfies these characteristics isshown in FIGS. 1, 9, and 10. In particular, the illustrated devices aregenerally planar in shape even though the device occupiesthree-dimensional space. Such devices may define a minor axis, aboutwhich the device is substantially symmetrical, and a major axis that issubstantially perpendicular to the minor axis. The device may have amaximum dimension in the direction of the major axis that does notexceed about 6 cm, and in particular embodiments is less than 5 cm, suchas about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or smaller. Thedevice may have a maximum dimension in the direction of the minor axisthat does not exceed about 4.5 cm, and in particular embodiments is lessthan 4 cm, such as about 3.5 cm, about 3 cm, or smaller. The device iscurved about substantially its entire exterior perimeter in both a majorcross-sectional plane and a minor cross-sectional plane. In other words,the overall exterior shape of the device is curved and thecross-sectional shape of the device is rounded. Thus, the device issubstantially devoid of edges, except for edges on the two flat ends,which are completely protected within the interior of the device whenthe device lies in a plane. These characteristics enable the device toreorient itself into a position of reduced compression when in the emptybladder.

The device also may be small enough in the retention shape to permitintravesical mobility. In particular, the device when deployed may besmall enough to move within the bladder, such as to move freely orunimpeded throughout the entire bladder under most conditions of bladderfullness, facilitating patient tolerance of the device. Free movement ofthe device also facilitates uniform drug delivery throughout the entirebladder, as opposed to a particular bladder location located near therelease orifice. However, devices that otherwise move freely within thebladder may be impeded from moving freely when the bladder is empty, andyet the device may still be tolerable if sufficiently compressible asdescribed above.

The device also may have a density that is selected to facilitatefloatation. The device has a minimum density in a dry and unloadedstate, meaning the device is not loaded with drug and fluid is notpresent in the device walls or lumens. The density of the device alsoincreases when the device is in a wet state, meaning fluid is present inthe device walls and lumens. The device enters the wet state uponimplantation in the bladder, as the device becomes surrounded by urine.In use, the device may have a maximum density after implantation, whenthe device is loaded with the maximum drug payload and liquid displacesany air present in the walls and lumens. Subsequently, the density ofthe device may remain essentially the same or decrease as the drug issolubilized and released, and replaced by urine.

In general, the device in the dry and loaded state may have a density inthe range of about 0.5 g/mL to about 1.5 g/mL, such as between about 0.7g/mL to about 1.3 g/mL. In some embodiments, the device in the dry andloaded has a density that is less than the density of water, such as adensity that is less than about 1 g/mL. Such densities facilitatebuoyancy and movement in the bladder. Lighter or lower density materialsmay be integrated into the device as needed to compensate for any higherdensity drug or other payload in the device, thereby maintaining anoverall density that facilitates buoyancy for tolerance purposes. Inaddition, air or another gas may be trapped in portions of the device toreduce the overall density. For example, the walls of retention framelumen may be made impermeable to water such that an air pocket is formedin the retention frame lumen about the elastic wire. A coating or sheathmay be applied to the walls, on either the inside or outside, to reducethe water permeability.

One example device may have a mass of about 0.40 grams or less and adensity of about 0.7 g/mL or less when unloaded. The device may beloaded with a drug having a mass of about 275 mg or less. In suchembodiments, the device when loaded may have a mass of about 0.675 gramsor less and a density of about 1.1 g/mL or less. Such a device may bewell tolerated in the bladder. Devices of smaller masses and densitieswould likewise be well tolerated. The device may also be somewhatlarger, for example, the L650 device described in Example 3 below.

The exact configuration and shape of the intravesical drug deliverydevice may be selected depending upon a variety of factors including thespecific site of deployment/implantation, route of insertion, drug,dosage regimen, and therapeutic application of the device. The design ofthe device may minimize the patient's pain and discomfort, while locallydelivering a therapeutically effective dose of the drug to a tissue site(e.g., urothelial tissue) in a patient.

The implantable drug delivery device can be made to be completely orpartially bioerodible so that no explanation, or retrieval, of thedevice is required following release of the drug formulation. As usedherein, the term “bioerodible” means that the device, or one or moreparts thereof, degrades in vivo by dissolution, enzymatic hydrolysis,erosion, resorption, or a combination thereof. In one embodiment, thisdegradation occurs at a time that does not interfere with the intendedkinetics of release of the drug from the device. For example,substantial erosion of the device may not occur until after the drugformulation is substantially or completely released. In anotherembodiment, the device is erodible and the release of the drugformulation is controlled at least in part by the degradation or erosioncharacteristics of the erodible device body.

Alternatively, the implantable drug delivery device may be at leastpartially non-bioerodible. In some embodiments, the device is formedfrom materials suited for urological applications, such as medical gradesilicone, natural latex, PTFE, ePTFE, PLGA, PGS, stainless steel,nitinol, elgiloy (non ferro magnetic metal alloy), polypropylene,polyethylene, polycarbonate, polyester, nylon, or combinations thereof.Following release of the drug formulation, the device and/or theretention frame may be removed substantially intact or in multiplepieces. In some embodiments, the device is partially bioerodible so thatthe device, upon partial erosion, breaks into non-erodible pieces smallenough to be excreted from the bladder. In another embodiment, thedevice may be collapsible following drug release, thereby facilitatingvoiding of the device in a substantially intact form. Usefulbiocompatible erodible and non-erodible materials of construction areknown in the art.

In a preferred embodiment, the drug delivery device is sterilized, suchas after the device is manufactured/assembled and before the device isimplanted. In some cases, the device may be sterilized after the deviceis packaged, such as by subjecting the package to gamma irradiation orethylene oxide gas.

The Drug Reservoir Portion

In one embodiment, the drug reservoir portion of the device includes anelongated tube. An interior of the tube may define one or more drugreservoirs, and a drug formulation may be housed in the drugreservoir(s). The drug reservoir portion may be provided in a form otherthan a tube.

The release rate of the drug from the drug reservoir portion generallyis controlled by the design of the combination of the device components,including but not limited to the materials, dimensions, surface area,and apertures of the drug reservoir portion, as well as the particulardrug formulation and total mass of drug load, among others.

An example of such a drug reservoir portion is shown in FIGS. 1-3. Asshown, the drug reservoir portion 102 may include a body formed from anelastomeric tube 122. The tube 122 defines a reservoir 108 that containsa number of drug tablets 112. Ends of the tube 122 may be sealed withsealing structures 120. At least one aperture 118 may be disposed in thetube 122. In cases in which an aperture 118 is provided, the aperture118 optionally may be closed by a degradable timing membrane, which maycontrol the initiation of release of the drug formulation from thereservoir. In some cases, a sheath or coating may be positioned about atleast a portion of the tube 122 to control or reduce the release rate,such as by reducing the osmotic surface area of the tube or by reducingdiffusion through the tube wall. For simplicity, the degradable timingmembranes and sheaths or coatings are not shown.

In one embodiment, the drug reservoir portion operates as an osmoticpump. In such embodiments, the tube may be formed from a water permeablematerial, such as a silicone, or tube may have a porous structure, orboth. Following implantation, water or urine permeates through the wallof the tube, one or more apertures formed through the tube, or one ormore passing pores formed through a porous tube. The water enters thereservoir, and is imbibed by the drug formulation. Solubilized drug isdispensed at a controlled rate out of the reservoir through the one ormore apertures, driven by osmotic pressure in the reservoir. Thedelivery rate and overall performance of the osmotic pump is affected bydevice parameters, such as the surface area of the tube; thepermeability to liquid of the material used to form the tube; the shape,size, number and placement of the apertures; and the drug formulationdissolution profile, among other factors. The delivery rate can bepredicted from the physicochemical parameters defining the particulardrug delivery system, according to well known principles, which aredescribed, for example, in Theeuwes, J. Pharm. Sci., 64(12):1987-91(1975). In some embodiments, the device may initially exhibit azero-order release rate and subsequently may exhibit a reduced,non-zero-order release rate, in which case the overall drug releaseprofile may be determined by the initial zero-order release rate and thetotal payload. Representative examples of osmotic pump designs, andequations for selecting such designs, are described in U.S. PatentPublication No. 2009/0149833 to Cima, et al.

In an alternative embodiment, the device may operate essentially bydiffusion of the drug from the tube through (i) one or more discreteapertures formed in the wall of the tube, or passing pores formed in thewall of a porous tube, or (ii) through the wall of the tube itself,which may be permeable to the drug, or (iii) a combination thereof. Inembodiments in which diffusion occurs through the wall, the apertures orpassing pores may not be included. In still other embodiments, thedevice may operate by a combination of osmosis and diffusion.

The drug reservoir portion may be formed from an elastomeric material,which may permit elastically deforming the device for its insertion intoa patient, e.g., during its deployment through deployment instrumentsuch as a cystoscope or catheter. For example, the tube may beelastically deformed along with the retention frame for intravesicalimplantation, as described in further detail below.

In a preferred embodiment, the drug reservoir portion is formed of amaterial that is both elastomeric and water permeable. One material thatis both elastomeric and water permeable is silicone, although otherbiocompatible materials may be used.

The length, diameter, and thickness of the tube may be selected based onthe volume of drug formulation to be contained, the desired rate ofdelivery of the drug from the tube, the intended site of implantation ofthe device within the body, the desired mechanical integrity for thedevice, the desired release rate or permeability to water and urine, thedesired induction time before onset of initial release, and the desiredmethod or route of insertion into the body, among others. The tube wallthickness may be determined based on the mechanical properties and waterpermeability of the tube material, as a tube wall that is too thin maynot have sufficient mechanical integrity while a tube wall that is toothick may experience an undesirably long induction time for initial drugrelease from the device.

In one embodiment, the device body is non-resorbable. It may be formedof a medical grade silicone tubing, as known in the art. Other examplesof suitable non-resorbable materials include synthetic polymers selectedfrom poly(ethers), poly(acrylates), poly(methacrylates), poly(vinylpyrolidones), poly(vinyl acetates), poly(urethanes), celluloses,cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers,poly(siloxanes), copolymers thereof, and combinations thereof.

In some embodiments, the device body is bioerodible. In one embodimentof a bioerodible device, the tube of the body is formed of abiodegradable or bioresorbable polymer. Examples of suitable suchmaterials include synthetic polymers selected from poly(amides),poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters),polyphosphazenes, pseudo poly(amino acids),poly(glycerol-sebacate)(PGS), copolymers thereof, and mixtures thereof.In a preferred embodiment, the resorbable synthetic polymers areselected from poly(lactic acids), poly(glycolic acids),poly(lactic-co-glycolic acids), poly(caprolactones), and mixturesthereof. Other curable bioresorbable elastomers includepoly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly (octane-diol citrate) (POC). PC-based polymersmay require additional cross-linking agents such as lysine diisocyanateor 2,2-bis(ε-caprolacton-4-yl)propane to obtain elastomeric properties.

The tube of a drug reservoir portion tube may be substantially linearand in some cases may be substantially cylindrical with a circularcross-section, although other polygonal cross-sectional shapes can beused.

The ends of the tube may be sealed to limit escape of the drug, such aswith a sealing structure or other sealing means. The sealing structuremay have any shape suited to plug or close the tube end, such as acylinder 120 as shown in FIG. 1, a ball, a disk, or others. The sealingstructure may have a larger diameter than the inner diameter of thetube, such that the tube stretches to fit snugly about the sealingstructure, closing the tube and retaining the sealing structure inplace. The sealing structure may be formed from biocompatible material,including a metal such as stainless steel, a polymer such as silicone, aceramic, sapphire, or adhesive, among others or combinations thereof.The material may be biodegradable or bioerodible. A medical gradesilicone adhesive or other adhesive also may be loaded into the tube ina workable form and may then cure within the tube to seal the end.

In some embodiments, the tube may have multiple reservoirs. Eachreservoir may be defined by a portion of the tube inner surface and atleast one partition. The partition may be a partition structure or pluginserted into the tube, such as a cylinder, sphere, or disk, amongothers, in which case the partition structure may have a largercross-section than the tube, securing the partition structure in placeand segregating adjacent reservoirs. For example, the cylindrical plug120 of FIG. 1 that closes the tube end may instead serve as a partitionstructure to segregate two reservoirs positioned adjacent to each otheralong the length of the tube. The partition may be non-porous orsemi-porous, non-resorbable or resorbable and may be formed of amaterial described above with reference to the cylindrical plug 120. Thepartition also may be formed in the tube, such as by molding. Forexample, one or more webs may extend through the tube along its lengthto segregate axial reservoirs that extend along the length of the tube,as shown in Examples J through L of FIG. 6. The partition also may be astructure that joins two different tubes that serve as separatereservoirs, as shown in Examples M through O of FIG. 6.

The multiple reservoirs permit segregating two or more different drugformulations in different reservoirs, delivering a single drug fromdifferent reservoirs at different rates or times following implantation,or combinations thereof. For example, two different reservoirs may havedifferent configurations, such as different materials, differentpermeabilities, different numbers or placements of apertures (or theabsence of apertures), different timing membranes in the apertures,among others or combinations thereof. The two different reservoirs alsomay house the same or different drug formulations in the same ordifferent forms (such as liquid, semi-solid, and solid), or combinationsthereof. The two different reservoirs further may be configured torelease drug via different release mechanisms, such as via osmosisthrough an aperture and by diffusion through a drug reservoir wall thatmay lack an aperture completely. Coatings or sheaths also may beprovided along different portions of a single drug reservoir or alongdifferent drug reservoirs housing the same or different drugformulations. The onset of release of two doses in different reservoirscan be staged by configuring the device accordingly, such as by usingdifferent materials for portions of the tube defining differentreservoirs, by associating the aperture(s) of different reservoirs withdifferent timing membranes, by placing drugs with different solubilitiesin the reservoirs, or by placing drugs with different forms in thereservoirs, such as a liquid form for immediate release and a solid formto be solubilized prior to release. Thus, the device may release somedrug relatively quickly after implantation while other drug mayexperience an induction time before beginning release. These embodimentscan be combined and varied to achieve the desired release profile of thedesired drug.

In one embodiment, the total volume of the reservoir (or combinedreservoirs) is sufficient to contain all of the drug needed for localdelivery over the course of a single treatment, reducing the number ofprocedures needed to treat a particular condition.

Apertures

In some embodiments, the device includes one or more apertures ororifices for dispensing the drug, such as via osmosis, diffusion, or acombination thereof, among other. The apertures may be spaced along thetube to provide a passageway for release of the drug formulation. Theapertures or orifices may be positioned through a sidewall or an end ofthe tube. The apertures may be in fluid communication with one or morereservoirs. Embodiments of apertures 118 are shown on the drug reservoirportions in FIGS. 1 and 3. The aperture may be located about a middle ofthe drug reservoir portion or adjacent to its exit. The apertures may bepositioned away from a portion of the tube that will be folded duringinsertion to limit tearing of degradable membranes on the apertures.

In embodiments in which the device includes a device body that definesboth drug reservoir and retention frame lumens, such as the embodimentshown in FIG. 3, the aperture or apertures may have various positions onthe wall of the drug reservoir lumen with reference to the wall of theretention frame lumen, as further described below.

The size, number, and placement of the apertures may be selected toprovide a controlled rate of release of the drug. A device that operatesprimarily as an osmotic pump may have one or more apertures sized smallenough to reduce diffusion of the drug through the aperture(s), yetlarge enough and spaced appropriately along the tube to reduce thebuildup of hydrostatic pressure in the tube. Within these constraints,the size and number of apertures for a single device (or reservoir) canbe varied to achieve a selected release rate. In exemplary embodiments,the diameter of the aperture is between about 20 μm and about 500 μm,such as between about 25 μm and about 300 μm, and more particularlybetween about 30 μm and about 200 μm. In one particular example, theaperture has a diameter between about 100 μm and about 200 μm, such asabout 150 μm. In embodiments where the device operates primarily bydiffusion, the apertures may be in this range or larger. A single devicemay have apertures of two or more different sizes. The aperture may becircular, although other shapes are possible and envisioned, with theshape typically depending on manufacturing considerations. Examples ofprocesses for forming the apertures include mechanical punching, laserdrilling, laser ablation, and molding. The aperture may slightly taperfrom an exterior to an interior of the tube, and the aperture may becreated either before or after the drug is loaded into the tube. Theaperture also may be formed in an orifice structure disposed in an endof the tube, such as a ruby or sapphire precision orifice structurefrom, for example, Bird Precision Orifices, Swiss Jewel Company.

In some embodiments, the drug reservoir portion may not have anyapertures, in which case the drug may be released via a releasemechanism other than osmosis, such as diffusion through the wall of thedrug reservoir portion. Similarly, a drug reservoir portion havingmultiple discrete drug reservoirs may have apertures associated withall, some, or none of the drug reservoirs, in which cases release fromthe different drug reservoirs may occur via different releasemechanisms.

In one embodiment, a degradable membrane, i.e., a timing membrane, isdisposed over or in the apertures (e.g., in register with the aperture)to control the onset of release of the drug formulation, as described inU.S. Publication No. 2009/0149833.

The Drug Formulation and Solid Drug Units

The drug formulation can include essentially any therapeutic,prophylactic, or diagnostic agent, such as one that would be useful todeliver locally to a body cavity or lumen or regionally about the bodycavity or lumen. The drug formulation may consist only of the drug, orone or more pharmaceutically acceptable excipients may be included. Thedrug may be a biologic. The drug may be a metabolite. As used herein,the term “drug” with reference to any specific drug described hereinincludes its alternative forms, such as salt forms, free acid forms,free base forms, hydrates, and solvates. Pharmaceutically acceptableexcipients are known in the art and may include lubricants, viscositymodifiers, surface active agents, osmotic agents, diluents, and othernon-active ingredients of the formulation intended to facilitatehandling, stability, dispersibility, wettability, and/or releasekinetics of the drug.

In a preferred embodiment, the drug formulation is in a solid orsemi-solid form in order to reduce the overall volume of the drugformulation and thereby reduce the size of the device, facilitatingimplantation. The semi-solid form may be, for example, an emulsion orsuspension; a gel or a paste. In many embodiments, the drug formulationdesirably includes no or a minimum quantity of excipient for the samereasons of volume/size minimization.

In some embodiments, the drug is a high solubility drug. As used herein,the term “high solubility” refers to a drug having a solubility aboveabout 10 mg/mL water at 37° C. In other embodiments, the drug is a lowsolubility drug. As used herein, the term “low solubility” refers to adrug having a solubility from about 0.01 mg/mL to about 10 mg/mL waterat 37° C. The solubility of the drug may be affected at least in part byits form. For example, a drug in the form of a water soluble salt mayhave a high solubility, while the same drug in base form may have a lowsolubility. One example is lidocaine, which has a high solubility ofabout 680 mg/mL when in the form of a lidocaine hydrochloridemonohydrate, a water-soluble salt, but has a low solubility of about 8mg/mL when in the form of lidocaine base. High solubility drugs may besuited for release due to an osmotic pressure gradient, such as via oneor more apertures or passing pores through the device wall, while lowsolubility drugs may be suited for release via diffusion, such asdirectly through the device wall or through one or more apertures orpassing pores in the device wall. Thus, the drug may be formulated tohave a high or low solubility depending on the intended release mode. Inone embodiment, the drug is formulated to improve its apparentsolubility in the implantation environment, such as its apparentsolubility in urine within the bladder.

In a particular embodiment, the devices provide pain relief to thepatient. A variety of anesthetic agents, analgesic agents, andcombinations thereof may be used. In embodiments, the device deliversone or more local anesthetic agents. The local anesthetic agent may be acocaine analogue. In particular embodiments, the local anesthetic agentis an aminoamide, an aminoester, or combinations thereof. Representativeexamples of aminoamides or amide-class anesthetics include articaine,bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine,lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.Representative examples of aminoesters or ester-class anestheticsinclude amylocaine, benzocaine, butacaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine, hexylcaine, larocaine, meprylcaine,metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine,propoxycaine, proxymetacaine, risocaine, and tetracaine. These localanesthetics typically are weak bases and may be formulated as a salt,such as a hydrochloride salt, to render them water-soluble, although theanesthetics also can be used in free base or hydrate form. Otheranesthetics, such as lontocaine, also may be used. The drug also can bean antimuscarinic compound that exhibits an anesthetic effect, such asoxybutynin or propiverine. The anesthetic agent may be provided incombination with other drugs, such as those described in U.S. PatentApplication Publication No. 2011/0152839 A1 to Cima, et al., which isincorporated herein by reference.

The analgesic agent may be a narcotic or non-narcotic agent.Representative examples of analgesics include acetaminophen,buprenorphine, butorphanol, codeine, dihydrocodeine, fentanyl, heroin,hydrocodone, hydromorphone, methadone, morphine, nicomorphine,oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, pyridium(phenazopyridine), thebaine, tramadol. The analgesic agent may beselected, for example, from non-opioid, non-steroidal analgesics, opioidanalgesics, and salicylates, among others types.

The drug may be an antispasmodic agent, such as hyoscyanime sulfate.

The anesthetic agent, analgesic agent, and antispasmodic agent may beadministered by themselves or in a combination, alone or in combinationwith other agents. The drugs may all be administered locally, or in somecases one or a combination of the drugs are administered systemically(e.g., orally) while another or the same drug is administered locally tothe pelvic area tissue site, such as the bladder.

In certain embodiments, the drug delivery device is used to treatinflammatory conditions such as interstitial cystitis, radiationcystitis, painful bladder syndrome, prostatitis, urethritis,post-surgical pain, and kidney stones. In one particular embodiment, thedrug delivery device is used in association with the placement of aureteral stent, such as to treat pain, urinary urgency or urinaryfrequency resulting from ureteral stent placement.

The excipient of the drug formulation may be a matrix material, selectedto modulate or control the rate of release of the drug from thereservoir. In one embodiment, the matrix material may be a resorbable ornon-resorbable polymer. In another embodiment, the excipient comprises ahydrophobic or amphiphilic compound, such as a lipid (e.g., a fattyacids and derivatives, mono-, di- and triglycerides, phospholipids,sphingolipids, cholesterol and steroid derivatives, oils, vitamins andterpenes). The drug formulation may provide a temporally modulatedrelease profile or a more continuous or consistent release profile.Other drugs and excipients may be used for other therapies.

In a preferred embodiment, the drug formulation is in solid form. Forexample, the drug formulation is formed into solid drug units that areloaded into the drug reservoir portion. Each of the drug units is asolid, discrete object that substantially retains a selectively impartedshape (at the temperature and pressure conditions to which the deliverydevice normally will be exposed during assembly, storage, and handlingbefore implantation). The drug units may be in the form of tablets,capsules, pellets, or beads, although other configurations are possible.For example, FIGS. 1 and 2 illustrate a number of the solid drug units112 that are suited for implantation loaded into the drug reservoirlumen 108 of the drug delivery device 100.

The solid drug units may be made by a direct compression or othertableting process, a molding process, or other processes known in thepharmaceutical arts. The solid drug unit may be a tablet or capsule. Thetablet optionally may be coated with one or more materials known in theart for protecting the tablets against destructive exposure to oxygen orhumidity during tablet handling, device assembly and storage; forfacilitating device loading; for aesthetics; or for facilitating,retarding, or otherwise controlling in vivo dissolution and drug releasecharacteristics. The drug formulation also may be loaded into the drugreservoir in workable form and may cure therein. Thereafter, thesolidified drug may be broken along the length of the drug reservoir toform the interstices or breaks that permit device deformation. Forexample, in embodiments in which the drug formulation is configured tobe melted and solidified, the drug formulation can be melted, injectedinto the drug reservoir in melted form, solidified in the drugreservoir, and broken into pieces in the drug reservoir to accommodatedevice deformation or movement. The drug formulation also may beextruded with the drug reservoir, may cure within the drug reservoir,and subsequently may be broken along the length of the reservoir toaccommodate device deformation. In another form, the drug unit may be ina semi-solid form.

The drug tablet includes a drug content and may include an excipientcontent. The drug content includes one or more drugs or activepharmaceutical ingredients (API), while the excipient content includesone or more excipients. The term “excipient” is known in the art, andrepresentative examples of excipients useful in the present drug unitsmay include ingredients such as binders, lubricants, glidants,disintegrants, colors, fillers or diluents, coatings and preservatives,as well as other ingredients to facilitate manufacturing, storing, oradministering the drug units. In one embodiment, the excipient contentcomprises an osmotic agent (e.g., urea), a solubilizer, or a combinationthereof. These may be particularly useful with low solubility drugs.

In order to maximize the amount of drug that can be stored in andreleased from a given drug delivery device of a selected (small) size,the drug unit preferably comprises a high weight fraction of drug orAPI, with a reduced or low weight fraction of excipients as are requiredfor tablet manufacturing and device assembly and use considerations. Forthe purposes of this disclosure, terms such as “weight fraction,”“weight percentage,” and “percentage by weight” with reference to drug,or API, refers to the drug or API in the form employed, such as in saltform, free acid form, free base form, or hydrate form. For example, adrug tablet that has 90% by weight of a drug in salt form may includeless than 90% by weight of that drug in free base form.

In one embodiment, the drug tablet is more than 50% by weight drug. In apreferred embodiment, 75% or more of the weight of the drug tablet isdrug, with the remainder of the weight comprising excipients, such aslubricants and binders that facilitate making the drug tablet. For thepurposes of this disclosure, the term “high weight fraction” withreference to the drug or API means that excipients constitute less than25 wt %, preferably less than 20 wt %, more preferably less than 15 wt%, and even more preferably less than 10 wt % of the drug tablet. Insome cases, the drug content comprises about 75% or more of the weightof the drug tablet. More particularly, the drug content may compriseabout 80% or more of the weight of the drug tablet. For example, thedrug content may comprise between about 85% and about 99.9% of theweight of the drug tablet. In some embodiments, the excipient contentcan be omitted completely.

In one embodiment, the drug and excipients are selected and the tabletformulated to be water soluble, so that the drug tablets can besolubilized when the device is located in vivo, to release thesolubilized drug. In a preferred embodiment, the drug tablets areformulated to be sterilizable, either within or outside of the drugdelivery device, without substantial or detrimental changes in thechemical or physical composition of the drug tablets. Such drug tabletsmay be quite different from conventional drug tablets, which typicallyinclude active ingredients that constitute less than 50% of the drugtablet content by weight, with the remainder of the drug tabletcomprising excipients that are often insoluble and/or may not be suitedfor conventional sterilization. In a preferred embodiment, the drugtablets are mini-tablets which comprise greater than 80% lidocainehydrochloride monohydrate.

The individual drug units may have essentially any selected shape anddimension that fits within the device. In one embodiment, the drug unitsare sized and shaped such that the drug reservoir portion issubstantially filled by a select number of drug units. Each drug unitmay have a cross-sectional shape that substantially corresponds to across-sectional shape of the drug reservoir portion. For example, thedrug units 112 are substantially cylindrical in shape as shown in FIGS.1 and 3 for positioning in the substantially cylindrical drug reservoirlumen 108 shown in FIG. 1. Once loaded, the drug units 112 substantiallyfill the drug reservoir lumen 108, forming the drug reservoir portion102.

In embodiments, the drug units are shaped to align in a row when housedin the drug reservoir. Each drug unit has a cross-sectional shape thatcorresponds to the cross-sectional shape of the drug reservoir, and eachdrug unit may have end face shapes that correspond to the end faces ofadjacent drug units. Thus, once the drug tablets are loaded in the drugreservoir, the line or row of drug tablets may substantially fill thedrug reservoir with interstices or breaks formed between adjacent drugunits. The interstices or breaks accommodate deformation or movement ofthe device, such as during deployment, while permitting the individualdrug units to retain their solid form. Thus, the drug delivery devicemay be relatively flexible or deformable despite being loaded with asolid drug, as each drug unit may be permitted to move with reference toadjacent drug units.

An example is shown in FIGS. 1-3, which illustrates the drug unit 112having circular flat end faces and a cylindrical side wall. Thus, thedrug unit 112 can be aligned in a row with other drug units 112 forloading into the cylindrical drug reservoir lumen 108 as shown in FIGS.1 and 2. When so loaded, the drug units 112 substantially fill the drugreservoir lumen 108, with interstices or breaks 116 formed between themto accommodate deformation or movement. The flat end faces permitpiecewise flexibility of the device while limiting the volume or spacewithin the drug reservoir portion that is devoted to the interstices orbreaks 116. Thus, the device can be substantially filled with solid drugwhile retaining its flexibility. Loading the device with a number ofdrug tablets 112, such as drug tablets that are relatively uniform insize and shape, beneficially permits manufacturing a device that behavesas expected in response to expected forces during and after implantationand exhibits expected drug release characteristics once implanted. Thatis, the tablet uniformity advantageously enables reproducibility inproducing the medical product and thereby generally provides reliable,repeatable drug release characteristics.

In embodiments in which the solid drug tablets are designed forinsertion or implantation in a lumen or cavity in the body, such as thebladder, via a drug delivery device, such as a device of the typedescribed above with reference to FIGS. 1-3, the drug tablets may be“mini-tablets” that are suitably sized and shaped for insertion througha natural lumen of the body, such as the urethra. The term “mini-tablet”herein generally indicates a solid drug tablet that is substantiallycylindrical in shape, having end faces that are relatively planar orflat and a side face that is substantially cylindrical. An examplemini-tablet is shown in FIG. 1. The mini-tablet 112 has a diameter,extending along the end face, in the range of about 1.0 to about 3.2 mm,such as between about 1.5 and about 3.1 mm. The mini-tablet has alength, extending along the side face, in the range of about 1.7 mm toabout 4.8 mm, such as between about 2.0 mm and about 4.5 mm.

In a preferred embodiment, the drug tablets include lidocaine. A drugdelivery device having drug tablets that primarily comprise lidocainemay be wholly deployed in the bladder of a patient in need of treatmentfor interstitial cystitis, neurogenic bladder, or pain, among others.Other diseases or conditions may also be treated using this device. Inother embodiments, other drugs, alone or in combination with lidocaine,may be used to treat interstitial cystitis or other diseases andconditions involving the bladder including pain of the bladder andurethra, spasm of the bladder and urethra, and detrusor instability andvoiding frequency and nocturia associated with and following any varietyof procedures used to evaluate, diagnosis or treat the bladder, urethra,or prostate gland. In another embodiment, the treatment methodsdescribed herein are used to provide post-procedural symptom relief.

The drug tablets can be sterilized before or after loading/assembly intoa drug delivery device, and the drug tablets possess a commerciallyreasonable shelf life. Once implanted, the composition of the drugtablets is appropriate for the intended route of administration, isstable in acidic conditions, and provides pre-selected, reproducibledrug release kinetics. For example, the drug tablets may be solubilizedin the bladder to continuously release drug at a suitably stable ratedrug over an extended period.

Although mini-tablets and other solid drug tablets are described aboveas having a high weight fraction of drug or API and a low weightfraction of excipients, the solid drug tablets may have any weightfraction of drug, especially in cases in which the tablet includes adrug that is extremely potent, a stabilizing agent, or an agent thatincreases the solubility of the drug, among others or combinationsthereof.

The Retention Frame Portion

The drug delivery device may include a retention frame portion. Theretention frame portion is associated with the drug reservoir portionand permits retaining the drug reservoir portion in the body, such as inthe bladder. The retention frame portion may include a retention framethat is deformable between a relatively expanded shape and a relativelylower-profile shape. For example, the retention frame may naturallyassume the relatively expanded shape, may be manipulated into therelatively lower-profile shape for insertion into the body, and mayspontaneously return to the relatively expanded shape upon insertioninto the body. The retention frame in the relatively expanded shape maybe shaped for retention in a body cavity, and the retention frame in therelatively lower-profile shape may be shaped for insertion into the bodythrough the working channel of a deployment instrument such as acatheter or cystoscope. To achieve such a result, the retention framemay have an elastic limit, modulus, and/or spring constant selected toimpede the device from assuming the relatively lower-profile shape onceimplanted. Such a configuration may limit or prevent accidentalexpulsion of the device from the body under expected forces. Forexample, the device may be retained in the bladder during urination orcontraction of the detrusor muscle.

In a preferred embodiment, the retention frame includes or consists ofan elastic wire. In embodiments, the elastic wire functions as a spring.The elastic wire may comprise a biocompatible shape-memory material or abiodegradable shape memory polymer as described in U.S. Pat. No.6,160,084 to Langer et al. The elastic wire also may include arelatively low modulus elastomer, which may be relatively less likely toirritate or cause ulcer within the bladder or other implantation siteand may be biodegradable so that the device need not be removed.Examples of low modulus elastomers include polyurethane, silicone,styrenic thermoplastic elastomer, and poly(glycerol-sebacate) (PGS). Theelastic wire may be coated with a biocompatible polymer, such as acoating formed from one or more of silicone, polyurethane, styrenicthermoplastic elastomer, Silitek, Tecoflex, C-flex, and Percuflex.

For example, in the embodiment shown in FIGS. 1-2, the retention frame114 is an elastic wire formed from a superelastic alloy, such asnitinol, and surrounded by the wall 124 of the retention frame lumen310, which forms a protective sheath about the retention frame 114.Thus, the wall 124 may be formed from a polymer material, such assilicone. In other embodiments, the retention frame may be an elasticwire formed from a superelastic alloy, such as nitinol, that is coveredin a polymer coating, such as a silicone sheath and is attached to thedrug reservoir portion.

In some embodiments, the retention frame lumen 110 may include theretention frame 114 and a filling material, such as a polymer filling.An example filling material is a silicone adhesive, such as MED3-4213 byNusil Technology LLC, although other filling materials may be used. Thefilling material may fill the void in the retention frame lumen 110about the retention frame 114. For example, the filling material may bepoured into the retention frame lumen 110 about the retention frame 114and may cure therein. The filling material may reduce the tendency ofthe drug reservoir lumen 108 to stretch along, or twist or rotate about,the retention frame 114, while maintaining the drug reservoir lumen 108in a selected orientation with reference to the retention frame 114. Thefilling material is not necessary, however, and may be omitted.

When the retention frame is in the relatively expanded shape, such asthe coiled shapes shown in FIG. 1, the device may occupy a space havingdimensions suited to impede expulsion from the bladder. When theretention frame is in the relatively lower-profile shape, such as theelongated shapes shown in FIG. 2, the device may occupy an area suitedfor insertion into the body, such as through the working channel of adeployment instrument. The properties of the elastic wire cause thedevice to function as a spring, deforming in response to a compressiveload but spontaneously returning to its initial shape once the load isremoved. The polymer coating may make the outer surface of the retentionframe relatively smooth and soft, reducing irritation of the bladder orother implantation site.

A retention frame that assumes a pretzel shape may be relativelyresistant to compressive forces. The pretzel shape essentially comprisestwo sub-circles, each having its own smaller arch and sharing a commonlarger arch. When the pretzel shape is first compressed, the larger archabsorbs the majority of the compressive force and begins deforming, butwith continued compression the smaller arches overlap, and subsequently,all three of the arches resist the compressive force. The resistance tocompression of the device as a whole increases once the two sub-circlesoverlap, impeding collapse and voiding of the device as the bladdercontracts during urination.

In embodiments in which the retention frame comprises a shape-memorymaterial, the material used to form the frame may “memorize” andspontaneously assume the relatively expanded shape upon the applicationof heat to the device, such as when exposed to body temperatures uponentering the bladder.

The retention frame may be in a form having a high enough springconstant to retain the device within a body cavity, such as the bladder.A high modulus material may be used, or a low modulus material.Especially when a low-modulus material is used, the retention frame mayhave a diameter and/or shape that provides a spring constant withoutwhich the frame would significantly deform under the forces ofurination. For example, the retention frame may include one or morewindings, coils, spirals, or combinations thereof, specifically designedto achieve a desirable spring constant, such as a spring constant in therange of about 3 N/m to about 60 N/m, or more particularly, in the rangeof about 3.6 N/m to about 3.8 N/m. Such a spring constant may beachieved by one or more of the following techniques: increasing thediameter of the elastic wire used to form the frame, increasing thecurvature of one or more windings of the elastic wire, and addingadditional windings to the elastic wire. The windings, coils, or spiralsof the frame may have a number of configurations. For example, the framemay be in a curl configuration comprising one or more loops, curls orsub-circles. The ends of the elastic wire may be adapted to avoid tissueirritation and scarring, such as by being soft, blunt, inwardlydirected, joined together, or a combination thereof.

Examples are shown in FIG. 5. The retention frame may have atwo-dimensional structure that is confined to a plane, athree-dimensional structure, such as a structure that occupies theinterior of a spheroid, or some combination thereof. In particular,Examples A through G illustrate frames comprising one or more loops,curls, or sub-circles, connected either linearly or radially, turning inthe same or in alternating directions, and overlapping or notoverlapping. Examples H through N illustrate frames comprising one ormore circles or ovals arranged in a two-dimensional or athree-dimensional configuration, the circles or ovals either closed oropened, having the same or different sizes, overlapping or notoverlapping, and joined together at one or more connecting points. Theretention frame portion also may be a three-dimensional structure thatis shaped to occupy or wind about a spheroid-shaped space, such as aspherical space, a space having a prorate spheroid shape, or a spacehaving an oblate spheroid shape. Examples O through R illustrateretention frame portions that are shaped to occupy or wind about aspherical space, with each retention frame portion shown above arepresentation of the frame in a sphere. The retention frame portion maygenerally take the shape of two intersecting circles lying in differentplanes as shown in Example O, two intersecting circles lying indifferent planes with inwardly curled ends as shown in Example P, threeintersecting circles lying in different planes as shown in Example Q, ora spherical spiral as shown in Example R. In each of these examples, theretention frame portion can be stretched to the linear shape fordeployment through a deployment instrument. The retention frame portionmay wind about or through the spherical space, or other spheroid-shapedspace, in a variety of other manners. One or both of the retention frameand retention housing may be omitted, in which case the retentionportion may be components of the drug portion itself, which may assumeor may be deformed into a retention shape, or the retention portion maybe an anchor associated with the drug portion. Other configurations aredescribed in the U.S. patent applications incorporated by referenceherein.

Other Device Features

The device may include at least one radio-opaque portion or structure tofacilitate detection or viewing (e.g., by X-ray imaging or fluoroscopy)of the device by a medical practitioner as part of the implantation orretrieval procedure.

The device may include a retrieval feature, such as a structure thatfacilitates removal of the device from the body cavity, for example forremoval of a non-resorbable device body following release of the drugformulation. One example of a retrieval feature is a string, formed of abiocompatible material. The string may be attached to a mid-portion oran end-portion of the drug delivery device. In some embodiments, thestring is sized to extend along the urethra from the bladder to theexterior of the body, in which case a proximal end of the string may bepositioned outside of the body once the device is positioned in thebladder. The string also may be shorter in size, so that once the deviceis positioned in the bladder, the proximal end of the string ispositioned in the urethra in a location that is reachable by aphysician. In either case, the device may be removed from the bladder byengaging the string to pull the device through the urethra. In otherembodiments, the string is sized to be wholly implanted in the bladderwith the device, in which case the string facilitates locating andgrasping the device within the bladder using a removal instrumentpositioned in the urethra, such as a cystoscope or catheter.

Combination of the Components

The drug reservoir portion and the retention frame portion areassociated with each other to form the drug delivery device. A varietyof different associations are envisioned. For example, the drugreservoir portion and the retention frame portion may be at leastpartially aligned. In other words, the drug reservoir portion may extendalong a portion or the entire length of the retention frame portion,substantially parallel or coincident with the retention frame portion.An example of such an embodiment is shown in FIGS. 1-3. FIG. 6 alsoillustrates several alternative embodiments in cross-section. As shownin Examples F, G, H, and I, the retention frame wire may extend alongeither an exterior surface of the drug reservoir wall, along an interiorsurface of the drug reservoir wall, through the drug reservoir wall, orwithin a reinforced area inside or outside of the wall. As shown inExamples J, K, and L, the elastic wire may also be positioned within theinterior of the tube supported by a web, which may partition the tubeinto multiple compartments. The web may be perforated or otherwisenon-continuous so that the compartments are in communication with eachother, or the web may be relatively continuous such that thecompartments are segregated from each other to form different reservoirsthat may be suited for holding different drug formulations. The web maybe formed from the same material as the tube, or from a material havinga different permeability to water or urine, depending on the embodiment.As shown in Examples M, N, and O, the elastic wire may be associatedwith multiple tubes, extending along or between the tubes. The elasticwire may be embedded in a reinforcement area that joins togethermultiple discrete tubes. The tubes may hold the same or different drugformulations and also may be formed from the same or different materialsof construction, such as materials that differ in permeability to urineor other aqueous or bodily fluids.

In other embodiments, the drug reservoir portion may be attached to onlyportion of the retention frame. The drug reservoir portion may havefirst and second end portions that are attached to a portion of theretention frame. The end portions of the drug reservoir may terminate atthe retention frame, the end portions may overlap the retention frame,or a combination thereof. The drug reservoir portion may be orientedwith reference to the retention frame portion such that the drugreservoir portion lies within the perimeter of the retention frameportion, beyond the perimeter of the retention frame portion, or acombination thereof. Additionally, a number of drug reservoir portionsmay be associated with a single retention frame portion. Examples Athrough E of FIG. 6 illustrate such embodiments.

In other embodiments, the drug reservoir portion and the retention frameportion may be the same component in some embodiments. In such cases,the device may comprise a tube formed in a configuration having asufficient spring constant to retain the device in the body, asdescribed above. Also, the drug reservoir portion may be wrapped aroundthe retention frame portion, one or any number of times. The embodimentsdescribed herein may be combined and varied to produce other drugdelivery devices that fall within the scope of the present disclosure.For example, the drug reservoir portion may be attached to any portionof the retention frame portion in any manner. Multiple drug reservoirportions may be provided, a single drug reservoir portion may bepartitioned, or a combination thereof, which may facilitate deliveringmultiple different drugs into the body, delivering different forms ofdrugs into the body, delivering drugs at varying rates into the body, ora combination thereof.

It is noted that the device 400 shown in FIG. 4 has a slightly differentshape and configuration than the device 100 shown in FIG. 1. Forexample, the ends of the device 400 are relatively straighter than theends of device 100. The straighter ends may result because the retentionframe of the device 400 has relatively straight end portions, while theretention frame of the device 100 has relatively curved end portions.Either retention frame shape can be used.

In the embodiment shown in FIG. 1, for example, the drug delivery device100 is suited for delivering a drug into the bladder. The drug reservoirlumen 108 may have an inner diameter of about 1.3 to about 3.3 mm, suchas about 1.5 to about 3.1 mm, an outer diameter of about 1.7 to about3.7 mm, such as about 1.9 to about 3.4 mm, and a length of about 12 to21 cm, such as about 14 to 16 cm. The drug reservoir lumen 108 may holdabout 10 to 100 cylindrical drug tablets, such mini-tablets. Themini-tablets may each having a diameter of about 1.0 to about 3.3 mm,such as about 1.5 to about 3.1 mm, and a length of about 1.5 to about4.7 mm, such as about 2.0 to about 4.5 mm. Such mini-tablets may have alidocaine payload of about 3.0 to about 40.0 mg. One particular exampleof a mini-tablet may have a diameter of about 1.52 mm, a length of about2.0 to 2.2 mm, and a mass of about 4.0 to 4.5 mg lidocaine. Anotherparticular example of a mini-tablet may have a diameter of about 2.16mm, a length of about 2.9 to 3.2 mm, and a mass of about 11.7 to 13.1 mglidocaine. Yet another particular example of a mini-tablet may have adiameter of about 2.64 mm, a length of about 3.5 to 3.9 mm, and a massof about 21.3 to 23.7 mg lidocaine. Still another particular example ofa mini-tablet may have a diameter of about 3.05 mm, a length of about4.1 to 4.5 mm, and a mass of about 32.7 to 36.9 mg lidocaine. However,other diameters, lengths, and masses can be used.

Within these ranges, the device may be designed to deliver between about150 mg and 1000 mg of lidocaine to the bladder, such as about 200 mg,about 400 mg, about 600 mg, or about 800 mg of lidocaine. For example, asmaller payload may be delivered from a smaller device or from a deviceloaded with fewer tablets, the remainder of the space in the devicebeing loaded with a spacer or filling material.

In one embodiment, the device has a 50 mg payload of lidocainehydrochloride monohydrate. The device may provide a release rate up toabout 5 mg/day (e.g., at day 3 or 4 after insertion into the bladder)over a treatment period.

In some embodiments, the amount of anesthetic or analgesic agenteffective to achieve a desired therapeutic effect is at least 50 mgreleased continuously over 48 or more hours. In other embodiments, theamount of anesthetic or analgesic agent effective to achieve a desiredtherapeutic effect is at least 100 mg released continuously over 48 ormore hours. In certain embodiments, the amount of anesthetic oranalgesic agent effective to achieve a desired therapeutic effect is atleast 150 mg released continuously over 48 or more hours. In oneembodiment, the amount of anesthetic or analgesic agent effective toachieve a desired therapeutic effect is at least 200 mg releasedcontinuously over 48 or more hours. In another embodiment, the amount ofanesthetic or analgesic agent effective to achieve a desired therapeuticeffect is at least 300 mg released continuously over 48 or more hours.In a further embodiment, the amount of anesthetic or analgesic agenteffective to achieve a desired therapeutic effect is at least 400 mgreleased continuously over 48 or more hours. In yet another embodiment,the amount of anesthetic or analgesic agent effective to achieve adesired therapeutic effect is at least 500 mg released continuously over48 or more hours. In a still further embodiment, the amount ofanesthetic or analgesic agent effective to achieve a desired therapeuticeffect is at least 600 mg released continuously over 48 or more hours.In these embodiments, the anesthetic or analgesic agent may compriselidocaine.

Method of Making the Device

An embodiment of a method of making an implantable drug delivery devicemay include forming a drug delivery device, forming a number of drugtablets, and loading the drug tablets into the drug delivery device. Inembodiments, forming the drug delivery device may include one or more ofthe following sub-steps: forming a device body, forming a retentionframe, associating the device body with the retention frame, and formingone or more apertures in the device body. Suitable methods are describedfor example in U.S. Patent Application Publication No. 2010/0330149 toDaniel, et al.; U.S. Patent Application Publication No. 2010/0331770 toLee et al., and U.S. Patent Application Publication No. 2011/0060309 toLee et al., which are incorporated herein by reference.

Use and Applications of the Device

The device may be implanted in a body cavity, such as the bladder oranother pelvic area organ or tissue structure, and subsequently mayrelease one or more drugs for the treatment of one or more conditions,locally to one or more tissues at the deployment site and/or regionallyto other tissues distal from the deployment site. The release may becontrolled over an extended period. Thereafter, the device may beremoved, resorbed, excreted, or some combination thereof.

In embodiments, the drug delivery device may be inserted into the bodyusing a deployment instrument. The drug delivery device may bereleasably associated with the deployment instrument. In one example,the device is inserted by passing the drug delivery device through adeployment instrument and releasing the device from the deploymentinstrument into the body. In cases in which the device is deployed intoa body cavity, or lumen, such as the bladder, the device assumes aretention shape, such as an expanded or higher profile shape, once thedevice emerges from the deployment instrument into the cavity. Anexample is illustrated in FIG. 7, which shows the device 700 assuming aretention shape as the device exits a deployment instrument 702. Thedeployment instrument 702 may be any suitable device. It may be alumenal device, such as a catheter, urethral catheter, or cystoscope.These terms are used interchangeably herein, unless otherwise expresslyindicated. The deployment instrument 1102 may be a commerciallyavailable device or a device specially adapted for the present drugdelivery devices.

Once implanted, the device may release the drug. The device may provideextended, continuous, intermittent, or periodic release of a desiredquantity of drug over a desired, predetermined time period. Inembodiments, the device can deliver the desired dose of drug over anextended period, such as 12 hours, 24 hours, 5 days, 7 days, 10 days, 14days, or 20, 25, 30, 45, 60, or 90 days, or more. The rate of deliveryand dosage of the drug can be selected depending upon the drug beingdelivered and the disease or condition being treated.

In embodiments in which the device comprises a drug in a solid form,elution of drug from the device occurs following dissolution of the drugwithin the device. Bodily fluid enters the device, contacts the drug andsolubilizes the drug, and thereafter the dissolved drug diffuses fromthe device or flows from the device under osmotic pressure or viadiffusion. For example, the drug may be solubilized upon contact withurine in cases in which the device is implanted in the bladder.

For purposes of clarity, it is noted that it not necessary that all ofthe drug dissolve before elution or release of the drug begins. In fact,once a portion of the drug dissolves, release of that portion may beginalmost immediately. Release of solubilized drug may occur beforeremaining portions of the drug are solubilized.

Subsequently, the device may be retrieved from the body, such as incases in which the device is non-resorbable or otherwise needs to beremoved. Retrieval devices for this purpose are known in the art or canbe specially produced. The device also may be completely or partiallybioresorbable, such that retrieval is unnecessary, as either the entiredevice is resorbed or the device sufficiently degrades for expulsionfrom the bladder during urination. The device may not be retrieved orresorbed until some of the drug, or preferably most or all of the drug,has been released. If needed, a new drug-loaded device may subsequentlybe implanted, during the same procedure as the retrieval or at a latertime.

FIG. 8 illustrates the implantation of a device 800 into the bladder,wherein the adult male anatomy is shown by way of example. A deploymentinstrument 802 may be inserted through the urethra to the bladder, andthe device 800 may be passed through the deployment instrument 802,driven by a stylet or flow of lubricant or other fluid, for example,until the device 800 exits into the bladder. Thus, the device isimplanted into the bladder of a male or female human patient in need oftreatment, either adult or child.

The device may be deployed into the bladder of a patient in anindependent procedure or in conjunction with another urological or otherprocedure or surgery, either before, during, or after the otherprocedure. The device may release one or more drugs that are deliveredto local and/or regional tissues for therapy or prophylaxis, eitherperi-operatively, post-operatively, or both.

In one embodiment, the implantable device, with a self-contained drugpayload, is deployed wholly within the bladder to provide local,sustained delivery of at least one drug locally to the bladder in aneffective amount. Following in vivo deployment of the device, at least aportion of the payload of drug is released from the device substantiallycontinually over an extended period, to the urothelium and possibly tonearby tissues, in an amount effective to provide treatment or toimprove bladder function in the patient. In a preferred embodiment, thedevice resides in the bladder releasing the drug over a predeterminedperiod, such as two weeks, three weeks, four weeks, a month, or more.

In such cases, the device may be used to treat interstitial cystitis,radiation cystitis, pelvic pain, overactive bladder syndrome, bladdercancer, neurogenic bladder, neuropathic or non-neuropathicbladder-sphincter dysfunction, infection, post-surgical pain,post-procedural (prostate, urethral, bladder) pain and spasm, irritativevoiding symptoms (sense of urgency, urinary frequency, nocturia) orother diseases, disorders, and conditions treated with drugs deliveredto the bladder. The device may deliver drugs that improve bladderfunction, such as bladder capacity, compliance, and/or frequency ofuninhibited contractions, that reduce pain and discomfort in the bladderor other nearby areas, or that have other effects, or combinationsthereof. The bladder-deployed device also may deliver a therapeuticallyeffective amount of one or more drugs to other genitourinary siteswithin the body, such as other locations within urological orreproductive systems of the body, including one or both of the kidneys,the urethra, one or both of the ureters, the penis, the testes, one orboth of the seminal vesicles, one or both of the vas deferens, one orboth of the ejaculatory ducts, the prostate, the vagina, the uterus, oneor both of the ovaries, or one or both of the fallopian tubes, amongothers or combinations thereof. For example, the intravesical drugdelivery device may be used in the treatment of kidney stones orfibrosis, erectile dysfunction, among other diseases, disorders, andconditions.

In some embodiments, the intravesical drug delivery device is deployedinto the bladder of a patient for regional drug delivery to one or morenearby genitourinary sites. The device may release drug locally to thebladder and regionally to other sites near the bladder. Such deliverymay provide an alternative to systemic administration, which may entailundesirable side effects or result in insufficient bioavailability ofthe drug.

In one embodiment, the intravesical drug delivery device is implantedinto a bladder to locally deliver a local anesthetic agent formanagement of pain and/or irritative voiding symptoms (urgency,frequency, nocturia) arising from any source, such as a disease ordisorder in genitourinary tissues, or pain stemming from any bladderprocedure, such as surgery, catheterization, ablation, medical deviceimplantation, or stone or foreign object removal, among others. Forexample, a local anesthetic agent can be released into the bladder forregional delivery to nearby sites to manage nearby pain arising from anysource, such as post-operative pain associated with the passage of amedical device into or through a ureter or other post-operative pain insites apart from the bladder.

In one particular embodiment, a device having a payload of lidocaine maybe delivered to the bladder, and lidocaine may be continuously releasedfrom the device over an extended period. In one embodiment, localdelivery of lidocaine to the urothelium of the bladder is provided fromthe presently disclosed devices which have been deployed into thebladder in a manner which achieves a sustained level of lidocaine abovethe concentration that could be obtained for an extended period viainstillation, yet without the high initial peak observed withinstillation and without significant systemic concentrations. Thereby, asmall payload may be implanted, reducing the risk of systemic effects inthe event of device failure. Implanting lidocaine in solid form permitsfurther reducing the size of the device to reduce bladder irritation andpatient discomfort. The lidocaine may be delivered without regard to thepH of the urine. In one embodiment, the device may have two payloads oflidocaine that are released at different times. The first payload may beadapted for relatively quick release, while the second payload may beadapted for more continuous release. For example, the first payload maybe in liquid form or may be housed in a relatively fast-acting osmoticpump, such as a silicone tube having a relatively thinner wall, whilethe second payload may be solid form or may be housed in an osmotic pumpthat experiences an initial delay or induction time before releasing,such as a silicone tube having a relatively thicker wall. Thus, themethod may continuously release lidocaine into the bladder during aninitial, acute phase and during a maintenance phase. Such a method maycompensate for an initial induction time of the device.

The present invention may be further understood with reference to thefollowing non-limiting examples.

Example 1 Diffusion of Drug Through the Wall of a Drug Reservoir

A study was performed to determine the feasibility of delivering drugthrough the wall of a drug reservoir via diffusion. Devices were formedform silicone tubes having an inner diameter of about 0.06 inches, anouter diameter of 0.08 inches, and a length of about 3 cm. The deviceswere loaded with solid drug tablets of lidocaine, for a total payload ofabout 60 mg. Some of the devices included an aperture formed through thetube wall, the aperture having a diameter of 150 μm. These devices wereloaded with solid tablets of either lidocaine hydrochloride monohydrateor a combination of lidocaine hydrochloride monohydrate and lidocainebase. Other devices did not include an aperture and were loaded withsolid drug tablets of lidocaine base. The devices were tested in vitroin water at about 37° C. Release profile data demonstrated that it isfeasible to deliver drug via diffusion through a silicone wall withoutan aperture. The release rate was relatively zero-order over a period ofabout four days, tapering off thereafter, with the release rate varyingbased on the device.

Another study was performed to investigate the feasibility of deliveringdrug from a device through both a wall of a drug reservoir and from anaperture in the wall of the drug reservoir. Devices were formed formsilicone tubes having a length of about 3 cm. The devices were loadedwith solid drug tablets of lidocaine base, for a total payload of about60 mg. Five devices had an inner diameter of about 0.060 inches and anouter diameter of 0.08 inches. The first device had one aperture with adiameter of about 150 μm, the second device had two apertures that eachhad a diameter of about 360 μm, the third device had thirty aperturesthat each had a diameter of about 360 μm, the fourth device had sixtyapertures that each had a diameter of about 360 μm, and the fifth devicehad no apertures. A sixth device had an inner diameter of about 0.06inches, an outer diameter of about 0.1 inches, and no apertures. Thedevices were tested in vitro in water at about 37° C. Release profiledata showed that lidocaine base can be released from a silicone tubewithout any apertures and that the release rate can be increased byadding apertures to the device.

Example 2 Effectiveness of Device Versus Daily Instillations ofLidocaine

An open-label, ascending dose, active-treatment cohort study wasconducted to investigate safety, tolerability, and limitedpharmacokinetic characterization of the device. The device wascytoscopically inserted into the bladders of 16 white, non-Hispanicfemale patients suffering from interstitial cystitis (IC) (2 patientswere treated in both cohorts). Nine patients in each cohort receiveddevices containing 200 mg and 650 mg of lidocaine, respectively. The 200mg and 650 mg devices contained 246 mg and 801 mg of lidocainehydrochloride monohydrate, respectively. The 200 mg device includedsilicone elastomer tubing, nitinol wire, and sapphire (aluminum oxide)balls. The 650 mg device included the same components, except thesapphire balls were replaced by silicone spacers and silicone adhesive.

On Day 1 of the test, a 200 mg or 650 mg device was inserted into thebladder of each patient. On Day 14±1, the devices were removed bycytoscopy. Each patient received a follow-up examination on Day 21±2 andDay 28±2.

Before insertion of the device, the participants scored their bladderpain and urinary urgency on a scale of “0 to 10” on a 10 cm line with 0and 10 representing “no pain or urgency” and “pain or urgency the worstyou can imagine,” respectively. The baseline results are shown in Table1, along with the baseline voiding frequency per 24 hours, baselinenocturia, interstitial cystitis symptom index (ICSI), and interstitialcystitis problem index (ICPI).

TABLE 1 Disease Criteria Scores Before Testing Criteria Baseline Score(±Stand. Dev.) Pain (0-10)  7.3 ± 1.4 Urgency (0-10)  7.7 ± 1.0 VoidingFrequency   19 ± 5.5 (Per 24 Hours)   Nocturia  5.0 ± 2.5 ICSI   14 ±3.24 ICPI 12.3 ± 3.04

The patients were asked to reassess the scores in Table 1 on Days 1, 2,3, 7, 10, 14±1, 21±2, and 28±2 of the study. On those same days, bloodand urine samples were collected and analyzed for lidocaine and itsmetabolite—2,6-xylidene—using separate validated LC-MS/MS assays. Theassays' results are shown in Tables 2, 3, and 4. Two patients in the 200mg device cohort did not meet the definition of PK evaluable and wereexcluded (hence, n=9-2=7), however, the full 650 mg device cohort wasevaluated (hence, n=9).

TABLE 2 Urinary Recovery Of Lidocaine (μg) and 2,6-Xylidene AfterInsertion 200 mg device (n = 7) 650 mg (n = 9) Lidocaine 2,6-XylideneLidocaine 2,6-Xylidene (μg) (μg) (μg) (μg) Day Mean SD Mean SD Mean SDMean SD 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 13455.55 1173.295.24 3.95 11194.72 9888.95 8.59 10.60 3 21371.86 1269.00 4.41 2.2842840.75 19949.81 17.74 25.53 7 5740.11 4538.56 1.45 0.95 18447.909407.19 13.58 13.44 10 3656.14 2440.04 0.25 0.44 15453.06 12889.94 6.347.70 14 2592.89 1553.65 0.00 0.00 4538.72 4601.83 3.66 7.34 21 5.0813.43 0.00 0.00 0.00 0.00 0.00 0.00 28 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00

TABLE 3 Urinary Recovery of Lidocaine (% dose) and 2,6-Xylidene AfterInsertion 200 mg device (n = 7) 650 mg (n = 9) Lidocaine 2,6-XylideneLidocaine 2,6-Xylidene (% dose) (% dose) (% dose) (% dose) Day Mean SDMean SD Mean SD Mean SD 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 6.730.59 0.01 0.00 1.72 1.52 0.00 0.00 3 10.69 0.63 0.00 0.00 6.59 3.07 0.010.01 7 2.87 2.27 0.00 0.00 2.84 1.45 0.00 0.00 10 1.83 1.22 0.00 0.002.38 1.98 0.00 0.00 14 1.30 0.78 0.00 0.00 0.70 0.71 0.00 0.00 21 0.000.01 0.00 0.00 0.00 0.00 0.00 0.00 28 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00

TABLE 4 Plasma Concentrations of Lidocaine and 2,6-Xylidene 200 mgdevice (n = 7) 650 mg (n = 9) Lidocaine 2,6-Xylidene Lidocaine2,6-Xylidene (ng/mL) (ng/mL) (ng/mL) (ng/mL) Day Mean SD Mean SD Mean SDMean SD 1 0.10⁺ 0.26 0.00 0.00 0.00 0.00 0.00 0.00 2 6.40 5.35 0.47 0.463.66 2.82 0.29 0.29 3 4.97 2.89 0.37 0.26 12.09 19.33 0.93 1.27 7 1.151.37 0.11 0.10 9.40 10.77 0.82 0.57 10 0.58 0.64 0.04 0.07 4.30 7.180.29 0.28 14 1.01 2.40 0.00 0.00 1.26 1.75 0.10 0.15 21 0.36⁺⁺ 0.880.03⁺⁺ 0.06 0.00 0.00 0.00 0.00 28 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 ⁺One patient had a lidocaine plasma concentration of 0.68 ng/mL.⁺⁺One patient had a lidocaine and 2,6-xylidene plasma concentration of2.15 and 0.15 ng/mL, respectively.

Based on urinary recovery and observed plasma concentrations in Tables2, 3, and 4 lidocaine was recovered in each test during the first 14days after insertion, suggesting that the drug was continuously releasedduring the entire period.

After the devices were removed on Day 14, the amount of lidocaine in theblood and urine samples quickly diminished. Tables 2 and 3 indicate thatan average of 5.08 μg and 0.00 μg of lidocaine were recovered on Days 21and 28, respectively, of the study. Both of these values represented0.00% of the original lidocaine dose. Table 4 indicates that the plasmaconcentrations of lidocaine diminished to zero by Days 21 and 28 afterremoval of the device on Day 14.

Despite the removal of the device on Day 14 and the subsequentdiminishment of lidocaine from the blood and urine samples, the patientsenjoyed sustained therapeutic benefits, including less pain and urgency,beyond Day 14 of the study.

FIG. 11 shows the sustained reduction in bladder pain that occurredthroughout the study for patients receiving the 200 mg device. The “0”line represents the baseline pain score of 7.3±1.4. Although the maximumchange from the baseline of −4.9±1.89 occurred on Day 10, reductions ofabout −3.6±3 and about −3.8±3 occurred on Days 21 and 28, respectively.The sustained reduction of the baseline pain score after Day 14suggested that the lidocaine's therapeutic effect extended beyond thetreatment period. The data in FIG. 11 contrasted with a trial thattested the effects of lidocaine bladder instillations given daily (1hour) for five days. The daily instillation trial showed a maximumbaseline reduction in bladder pain of only −2.38±2.67 (Nickel, J. Curtiset al. “Intravesical alkalinized lidocaine (PSD597) offers sustainedrelief from symptoms of interstitial cystitis and painful bladdersyndrome,” Journal Compilation, BJU International 103, 2008,910-918)(hereinafter “Plethora”).

A sustained reduction of baseline urgency scores also was observed. FIG.12 shows that the sustained reduction in urinary urgency that occurredthroughout the study for the patients receiving the 200 mg device. The“0” line represents the baseline urgency score of 7.7±1.0. Although themaximum change from baseline of −7.0±1.08 occurred on Day 14, reductionsof about −4.4±3.6 and about −5.2±3 occurred on Days 21 and 28,respectively. Once again, the data in FIG. 12 represented a significantimprovement over Plethora's daily instillation test, which showed amaximum reduction in urinary urgency of only −2.09±2.14.

The frequency of voiding also was reduced almost immediately afterdevice deployment and was sustained after the device removal on Day 14,as shown in FIG. 13. The “0” line represents the baseline voidingfrequency of 19±5.5. From Day 3 to Day 28, the device reduced theaverage voiding frequency by about −8.0±3.9 despite the removal of thedevice on Day 14. In contrast, Plethora's daily instillation testreduced voiding frequency by −1.69±7.62 only.

The device also reduced baseline nocturia by an average of about 3±2.2by Day 14. As shown in FIG. 14, the device reduced nocturia soon afterdeployment and maintained a sustained effect after its removal on Day14. Nocturia data were not collected in the Plethora trial.

The Plethora trial did show that baseline reduction in ICSI withlidocaine instillations was not sustained following completion oftreatment. The baseline ICSI in the Plethora trial was 13.67±2.99 and13.60±3.09. The baseline (“0” line) ICSI in the current trial was14±3.24, which was consistent with severe disease and similar to thebaseline in the Plethora trial. Unlike the Plethora trial's dailyinstillations, however, the 200 mg device caused a sustained reductionin baseline ICSI after the device was removed from the bladder. Thebaseline reduction of ICSI throughout the study is shown in FIG. 15.FIG. 16 shows the proportion of “ICSI Responders” in the cohort at eachtime point. An “ICSI Responder” was defined as a patient with a 30% orgreater improvement from the baseline score.

Similarly, the 200 mg device caused a sustained reduction in the ICPIthroughout the study, including after the removal of the device on Day14. The baseline (“0” line) ICPI was 12.3±3.04, which is shown as the“0” line in FIG. 17. As shown in FIG. 17, the average baseline reductionof ICPI caused by the 200 mg device averaged more than about −4 from Day3 to Day 28. The proportion of “ICPI Responders” in the cohort at eachtime point is shown in FIG. 18. An “ICPI Responder” is defined as onewith a 30% or greater improvement from baseline score. In contrast, thePlethora trial had a baseline ICPI of 12.09±2.50 and 12.22±2.28, but themean baseline reductions on Days 8 and 15 were only −3.82±3.61 and−3.36±3.90, respectively.

A Global Response Assessment (GRA) test also was administered to thepatients at Days 2, 3, 7, 10, 14, 21, and 28. A GRA is a seven itemLikert scale where patients report their overall response as (1)markedly worse, (2) moderately worse, (3) mildly worse, (4) no change,(5) mildly improved, (6) moderately improved, or (7) markedly improved.A “Responder” is a patient whose response is either “moderately” or“markedly improved.” The percentage of “Responders” at each time pointis shown in FIG. 19, and averaged about 50% or more on Days 3 through28. In the Plethora trial, instillations of lidocaine—even whenadministered daily for five days—induced responses of “moderately” or“markedly” global improvement in 44-63% of IC patients when tested in asimilar open-label design.

Example 3 Release Rate of Lidocaine from Device

The release rate of lidocaine from the 200 mg and 650 mg devices ofExample 2 was measured in vitro by simulating bladder conditions. Tables5 and 6 depict the average lidocaine release rate (mg free baseequivalent (FBE)/day) over 14 days.

TABLE 5 Release Rate of Lidocaine From 200 mg Device Average LidocaineRelease Elapsed Time (days) Rate (mg FBE/day) 1 17.9 2 26.9 3 22.1 414.6 7 7.3 8 6.3 9 4.0 10 4.4 11 3.2 14 3.3 Average 11 mg/day

TABLE 6 Release Rate of Lidocaine From 650 mg Device Average LidocaineRelease Elapsed Time (days) Rate (mg FBE/day) 1 24.9 2 46.4 3 59.7 633.8 7 21.9 8 19.8 9 17.6 10 10.2 13 13.1 14 12.2 Average 26 mg/day

The cumulative lidocaine release rates and lidocaine release rates forthe 200 mg and 650 mg devices are plotted in FIGS. 20 and 21, and FIGS.22 and 23, respectively.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

1. A medicament comprising lidocaine for use in the treatment of chronicpelvic pain, vulvodynia, orchialgia, urethral syndrome, dysparenia,chronic prostatitis, chronic pelvic pain, levator ani syndrome,irritative bowel syndrome, or a combination thereof by continuous orcontinual administration into the bladder of a patient over a treatmentperiod of 24 hours or more in an amount effective to achieve atherapeutic effect in another organ or tissue structure by means ofshared or convergent pelvic afferent pathways.
 2. The medicament ofclaim 1, wherein the duration of administration is from 2 to 28 days. 3.The medicament of claim 1, for use by continuous administration into thepatient's bladder at a mean average amount of from about 5 mg to about30 mg lidocaine (FBE) per day.
 4. The medicament of claim 3, wherein theduration of administration is from 2 to 28 days.
 5. The medicament ofclaim 1, wherein the cumulative amount of lidocaine (FBE) released intothe bladder over the treatment period is from about 20 mg to about 400mg.
 6. The medicament of claim 5, wherein the duration of release isfrom 10 to 14 days.
 7. The medicament of claim 1, wherein the rate oflidocaine (FBE) released into bladder is from 15 mg to 30 mg day per dayover the first 1 to 4 days of the treatment period and then tapers to arate of from 15 mg to 3 mg per day over the remainder of the treatmentperiod.
 8. The medicament of claim 7, wherein the measurable plasmaconcentration of lidocaine does not exceed 65 ng/ml at a time of peaklidocaine exposure in the bladder.
 9. The medicament of claim 1, for useby continuous administration wherein the rate of lidocaine (FBE)released into bladder is from 25 mg to 60 mg day per day over the first1 to 6 days of the treatment period and then tapers to a rate of from 25mg to 10 mg per day over the remainder of the treatment period.
 10. Themedicament of claim 9, wherein the measurable plasma concentration oflidocaine does not exceed 65 ng/ml at a time of peak lidocaine exposurein the bladder.
 11. The medicament of claim 1, for use by continuousrelease from a device wholly deployed into the bladder of the patientduring the treatment period.
 12. The medicament of claim 1, for use byrelease through a urethral catheter inserted in the bladder during thetreatment period.
 13. The medicament of claim 1, for use by continuousrelease from a coating substance that is transurethrally applied to thebladder wall, the coating substance comprising lidocaine and one or moreexcipient materials that promote adherence of the coating substance tothe wall of the bladder and provides continuous controlled release ofthe lidocaine over the treatment period.
 14. The medicament of claim 1,for use by continuous administration wherein the therapeutic effect issustained more than 48 hours beyond the end of the treatment period. 15.A method of treating a patient, the method comprising: locallyadministering to a pelvic-area organ or tissue structure in the patientat least one drug continuously or continually over a treatment period of24 hours or more in an amount effective to achieve a therapeutic effectin another organ or tissue structure by means of shared or convergentpelvic afferent pathways.
 16. The method of claim 15, wherein thepatient is diagnosed to have at least one of the following: IC/BPS,chronic pelvic pain, vulvodynia, orchialgia, urethral syndrome,dysparenia, chronic prostatitis, chronic pelvic pain, levator anisyndrome, irritative bowel syndrome, or a combination thereof.
 17. Themethod of claim 15, wherein the at least one drug comprises ananesthetic agent, an analgesic agent, an antispasmodic agent, anantimuscarinic agent, or a combination thereof.
 18. The method of claim15, wherein the pelvic-area organ or tissue structure comprises thebladder.
 19. The method of claim 15, wherein the drug is released from adrug delivery device or a sustained release composition deployed insidethe bladder.
 20. The method of claim 15, wherein the drug compriseslidocaine.
 21. A method of treating a patient, the method comprising:diagnosing in a patient at least one of IC/BPS, chronic pelvic pain,vulvodynia, orchialgia, urethral syndrome, dysparenia, chronicprostatitis, levator ani syndrome, irritative bowel syndrome, and acombination thereof; and administering locally to a pelvic-area organ ortissue structure in the patient at least one drug selected from thegroup consisting of anesthetic agents, analgesic agents, antispasmodicagents, antimuscarinic agents, and combinations thereof, wherein the atleast one drug is administered continuously over a treatment period of24 hours or more in an amount effective to achieve a therapeutic effectwhich is sustained beyond the end of the treatment period.
 22. Themethod of claim 21, wherein the pelvic-area organ or tissue structurecomprises the bladder.
 23. The method of claim 22, wherein the drug isreleased from a drug delivery device or a sustained release compositiondeployed inside the bladder.
 24. The method of claim 23, wherein thedrug comprises lidocaine.
 25. The method of claim 21, wherein the atleast one drug provides a therapeutic effect in (i) the pelvic-areaorgan or tissue structure in which the at least one drug isadministered, and (ii) at least one other organ or tissue of the pelvicarea.
 26. The method of claim 21, wherein the anesthetic or analgesicagent does not provide a therapeutic effect in the pelvic-area organ ortissue structure in which the anesthetic or analgesic agent isadministered, but does provide a therapeutic effect in at least oneother organ or tissue of the pelvic area.
 27. The method of claim 21,wherein the therapeutic effect is provided by pelvic afferent neuronalcrosstalk, cross-sensitization, or both.
 28. The method of claim 21,wherein the therapeutic effect comprises reducing pain.
 29. A method oftreating a patient diagnosed as having vulvodynia, orchialgia, urethralsyndrome, dysparenia, chronic prostatitis, chronic pelvic pain, levatorani syndrome, irritative bowel syndrome, or a combination thereof, themethod comprising: administering lidocaine or another anesthetic agentinto the bladder of the patient continuously or continually over atreatment period of 24 hours in an amount effective to achieve, bypelvic afferent neuronal crosstalk, cross-sensitization, or both, atherapeutic effect in a pelvic-area organ or tissue structure other thanthe bladder.
 30. The method of claim 29, wherein the lidocaine oranother anesthetic agent is administered into the bladder by releasefrom a drug delivery device or a sustained release composition deployedinside the bladder.